Huang Shanshan, Wang Xinru, Wang Meng, Lin Jinhong, Ren Jiaoqi, Lu Chenyu, Fu Jiayu, Zhang Yanli, Wang Xuechun, Xiao Jichang, Guo Jingchun, Zhou Houguang
Department of Geriatric of Huashan Hospital, National Clinical Research Center for Aging and Medicine, Fudan University, Shanghai, China.
State Key Laboratory of Fluorine and Nitrogen Chemistry and Advanced Materials, Chinese Academy of Sciences, Shanghai, China.
CNS Neurosci Ther. 2025 May;31(5):e70417. doi: 10.1111/cns.70417.
Diabetes-associated cognitive impairment (DACI) is a common complication of Type 2 diabetes mellitus (T2DM), with its mechanisms and treatments for DACI remaining incompletely clarified. This study investigated the protective efficacy of the novel lipid S-enantiomer of 9-palmitic acid esters of hydroxy stearic acids (S-9-PAHSA, S9P) in a high-fat diet-induced DACI mouse model.
Mice were randomly assigned to three groups: normal diet (ND), high-fat diet (HFD), and HFD + 30 mg/kg/day S9P (HFD + S9P). Fasting blood glucose (FBG), intraperitoneal glucose tolerance test (IPGTT), and insulin tolerance test (ITT) were conducted to assess blood glucose homeostasis. Morris Water Maze and Y maze tests evaluated cognitive function, and neuronal status was examined through pathological analysis, Golgi staining, and transmission electron microscopy (TEM). Colonic barrier integrity was assessed using periodic acid-Schiff and Alcian blue staining (AB-PAS) and immunohistochemistry (IHC) staining. Intestinal microbiota composition was analyzed by 16S rDNA sequencing, and serum metabolic characteristics were determined by metabolomics sequencing.
S9P improved glucose homeostasis and alleviated cognitive decline in DACI mice. It also mitigated neuronal damage, dendritic degeneration, and synaptic damage, while restoring colonic barrier integrity and ameliorating gut microbiome imbalances, insulin resistance, and lipid imbalance. Additionally, S9P regulated metabolite profiles and the PI3K/AKT/mTOR signaling pathways, and reduced astrocyte activation and neuroinflammatory responses in the hippocampus of HFD-induced DACI mice.
S9P had a protective effect against HFD-induced diabetic cognitive impairment closely related to the modulation of the gut-brain axis, suggesting that S9P has the potential to become a new therapeutic approach for DACI.
糖尿病相关认知障碍（DACI）是2型糖尿病（T2DM）的常见并发症，其发病机制及治疗方法仍未完全阐明。本研究在高脂饮食诱导的DACI小鼠模型中，探究新型脂质羟基硬脂酸9-棕榈酸酯的S-对映体（S-9-PAHSA，S9P）的保护作用。
将小鼠随机分为三组：正常饮食（ND）组、高脂饮食（HFD）组和高脂饮食+30mg/kg/天S9P（HFD+S9P）组。通过空腹血糖（FBG）、腹腔葡萄糖耐量试验（IPGTT）和胰岛素耐量试验（ITT）评估血糖稳态。采用莫里斯水迷宫和Y迷宫试验评估认知功能，并通过病理分析、高尔基染色和透射电子显微镜（TEM）检查神经元状态。使用过碘酸希夫和阿尔辛蓝染色（AB-PAS）及免疫组织化学（IHC）染色评估结肠屏障完整性。通过16S rDNA测序分析肠道微生物群组成，并通过代谢组学测序确定血清代谢特征。
S9P改善了DACI小鼠的血糖稳态，减轻了认知功能下降。它还减轻了神经元损伤、树突退化和突触损伤，同时恢复了结肠屏障完整性，改善了肠道微生物群失衡、胰岛素抵抗和脂质失衡。此外，S9P调节了代谢物谱和PI3K/AKT/mTOR信号通路，并减少了高脂饮食诱导的DACI小鼠海马体中的星形胶质细胞活化和神经炎症反应。
S9P对高脂饮食诱导的糖尿病认知障碍具有保护作用，这与肠-脑轴的调节密切相关，表明S9P有潜力成为DACI的一种新的治疗方法。
